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Apoptosis of Central and Peripheral Neurons Can Be Prevented with Cyclin‐Dependent Kinase/Mitogen‐Activated Protein Kinase Inhibitors
Author(s) -
Maas James W.,
Horstmann Sonja,
Borasio Gian Domenico,
Anneser Johanna M. H.,
Shooter Eric M.,
Kahle Philipp J.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.70041401.x
Subject(s) - ask1 , cyclin dependent kinase 5 , cyclin dependent kinase 2 , cyclin dependent kinase 9 , cyclin dependent kinase 4 , protein kinase a , mitogen activated protein kinase kinase , map kinase kinase kinase , microbiology and biotechnology , mitogen activated protein kinase , map2k7 , kinase , protein kinase r , chemistry , biology
Previous studies have indicated that certain members of the cyclin‐dependent kinase/mitogen‐activated protein kinase superfamily are involved in apoptosis of neuronal cells. Here, we have examined programmed cell death induced by withdrawal of neurotrophic support from CNS (rat retinal) and PNS (chick sympathetic, sensory, and ciliary) neurons. All four neuron types were equally rescued by the purine analogues olomoucine and roscovitine. Olomoucine inhibits multiple cyclin‐dependent and mitogen‐activated protein kinases with similar potency. Roscovitine is a more selective cyclin‐dependent kinase inhibitor; but, so is butyrolactone I, which did not prevent retinal ganglion cell death. The specific p38 MAPK inhibitor SB‐203580 did not prevent apoptosis in retinal ganglion cells. Death of these cells in the absence of neurotrophic factors was accompanied by morphological changes indicative of apoptosis, including nuclear condensation and fragmentation. Treatment with olomoucine or roscovitine not only prevented these apoptotic changes in retinal ganglion cells but also blocked neurite outgrowth. The survival‐promoting activity of olomoucine correlated with its in vitro IC 50 for c‐Jun N‐terminal kinase‐1 and its potency to repress c‐ jun induction in live PC12 cells. Roscovitine was more potent in rescuing neurons than in inhibiting Jun kinase. Thus, the antiapoptotic action of roscovitine might be due to inhibition of additional kinases.